Multistable and multistep dynamics in neutrophil differentiation.
Multistable and multistep dynamics in neutrophil differentiation.
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DOI：
10.1186/1471-2121-7-11
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发表时间：
2006-02-28
期刊：
影响因子：
--
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Chang HH;Oh PY;Ingber DE;Huang S
长期以来，细胞分化一直被认为是一个生物系统的开关，最近在微生物中的实验工作揭示了小基因调控回路中的生物动力学。然而，哺乳动物细胞分化的动力学还没有被分析的双稳态。在这里，我们研究了HL 60早幼粒细胞前体细胞如何过渡到中性粒细胞系的分化诱导剂，二甲基亚砜（DMSO）刺激后。分化标记物CD 11b（Mac-1）的表达动力学的单细胞分析揭示了全或无开关样行为，与作为群体平均值测量时的表达的看似渐进的变化相反。从前体到分化状态的进展被检测为在双峰分布中可区分的低（CD 11bLow）和高（CD 11bHigh）表达子亚群之间的离散过渡。CD 11b表达对DMSO剂量依赖性的滞后表明，这种双峰性可能反映了免疫动力学。但是，当分离和培养处于双模态模式的“未转换”（CD 11bLow）细胞亚群时，发现这些细胞与未分化的前体细胞不同，因为它们是“启动”分化的。这些发现表明，人HL 60细胞分化为中性粒细胞并不像传统模型那样是由一个简单的开关状态转换引起的。相反，哺乳动物的分化似乎是一个高维系统中的多步骤过程，这一结果与细胞复杂的潜在基因调控网络的高度连通性一致。
Cell differentiation has long been theorized to represent a switch in a bistable system, and recent experimental work in micro-organisms has revealed bistable dynamics in small gene regulatory circuits. However, the dynamics of mammalian cell differentiation has not been analyzed with respect to bistability. Here we studied how HL60 promyelocytic precursor cells transition to the neutrophil cell lineage after stimulation with the differentiation inducer, dimethyl sulfoxide (DMSO). Single cell analysis of the expression kinetics of the differentiation marker CD11b (Mac-1) revealed all-or-none switch-like behavior, in contrast to the seemingly graduated change of expression when measured as a population average. Progression from the precursor to the differentiated state was detected as a discrete transition between low (CD11bLow) and high (CD11bHigh) expressor subpopulations distinguishable in a bimodal distribution. Hysteresis in the dependence of CD11b expression on DMSO dose suggests that this bimodality may reflect a bistable dynamic. But when an "unswitched" (CD11bLow) subpopulation of cells in the bistable/bimodal regime was isolated and cultured, these cells were found to differ from undifferentiated precursor cells in that they were "primed" to differentiate. These findings indicate that differentiation of human HL60 cells into neutrophils does not result from a simple state transition of a bistable switch as traditionally modeled. Instead, mammalian differentiation appears to be a multi-step process in a high-dimensional system, a result which is consistent with the high connectivity of the cells' complex underlying gene regulatory network.
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DOI：
10.1073/pnas.0500345102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Kramer, BP;Fussenegger, M
通讯作者：
Fussenegger, M
影响因子：
16
作者：
de Krom, M;van de Corput, M;Strouboulis, J
通讯作者：
Strouboulis, J
影响因子：
13.8
作者：
Laurent, M;Kellershohn, N
通讯作者：
Kellershohn, N
DOI：
10.1073/pnas.77.5.2936
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BREITMAN, TR;SELONICK, SE;COLLINS, SJ
通讯作者：
COLLINS, SJ
DOI：
10.1073/pnas.75.5.2458
发表时间：
1978-01-01
影响因子：
11.1
作者：
COLLINS, SJ;RUSCETTI, FW;GALLO, RC
通讯作者：
GALLO, RC